| 1. |
- Chen, Zhishan, et al.
(författare)
-
Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
-
Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
|
|
| 2. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
-
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
-
Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
|
|
| 3. |
- Jung, Christian, et al.
(författare)
-
A comparison of very old patients admitted to intensive care unit after acute versus elective surgery or intervention
- 2019
-
Ingår i: Journal of critical care. - : W B SAUNDERS CO-ELSEVIER INC. - 0883-9441 .- 1557-8615. ; 52, s. 141-148
-
Tidskriftsartikel (refereegranskat)abstract
- Background: We aimed to evaluate differences in outcome between patients admitted to intensive care unit (ICU) after elective versus acute surgery in a multinational cohort of very old patients (80 years; VIP). Predictors of mortality, with special emphasis on frailty, were assessed.Methods: In total, 5063 VIPs were induded in this analysis, 922 were admitted after elective surgery or intervention, 4141 acutely, with 402 after acute surgery. Differences were calculated using Mann-Whitney-U test and Wilcoxon test. Univariate and multivariable logistic regression were used to assess associations with mortality.Results: Compared patients admitted after acute surgery, patients admitted after elective surgery suffered less often from frailty as defined as CFS (28% vs 46%; p < 0.001), evidenced lower SOFA scores (4 +/- 5 vs 7 +/- 7; p < 0.001). Presence of frailty (CFS >4) was associated with significantly increased mortality both in elective surgery patients (7% vs 12%; p = 0.01), in acute surgery (7% vs 12%; p = 0.02).Conclusions: VIPs admitted to ICU after elective surgery evidenced favorable outcome over patients after acute surgery even after correction for relevant confounders. Frailty might be used to guide clinicians in risk stratification in both patients admitted after elective and acute surgery.
|
|
| 4. |
- Bayer, Anita D., et al.
(författare)
-
Uncertainties in the land-use flux resulting from land-use change reconstructions and gross land transitions
- 2017
-
Ingår i: Earth System Dynamics. - : Copernicus GmbH. - 2190-4979 .- 2190-4987. ; 8:1, s. 91-111
-
Tidskriftsartikel (refereegranskat)abstract
- Land-use and land-cover (LUC) changes are a key uncertainty when attributing changes in measured atmospheric CO2 concentration to its sinks and sources and must also be much better understood to determine the possibilities for land-based climate change mitigation, especially in the light of human demand on other land-based resources. On the spatial scale typically used in terrestrial ecosystem models (0.5 or 1°) changes in LUC over time periods of a few years or more can include bidirectional changes on the sub-grid level, such as the parallel expansion and abandonment of agricultural land (e.g. in shifting cultivation) or cropland-grassland conversion (and vice versa). These complex changes between classes within a grid cell have often been neglected in previous studies, and only net changes of land between natural vegetation cover, cropland and pastures accounted for, mainly because of a lack of reliable high-resolution historical information on gross land transitions, in combination with technical limitations within the models themselves. In the present study we applied a state-of-The-Art dynamic global vegetation model with a detailed representation of croplands and carbon-nitrogen dynamics to quantify the uncertainty in terrestrial ecosystem carbon stocks and fluxes arising from the choice between net and gross representations of LUC. We used three frequently applied global, one recent global and one recent European LUC datasets, two of which resolve gross land transitions, either in Europe or in certain tropical regions. When considering only net changes, land-use-Transition uncertainties (expressed as 1 standard deviation around decadal means of four models) in global carbon emissions from LUC (ELUC) are ±0.19, ±0.66 and ±0.47gCa1 in the 1980s, 1990s and 2000s, respectively, or between 14 and 39% LUC. Carbon stocks at the end of the 20th century vary by ±11 PgC for vegetation and ±37PgC for soil C due to the choice of LUC reconstruction, i.e. around 3% of the respective C pools. Accounting for sub-grid (gross) land conversions significantly increased the effect of LUC on global and European carbon stocks and fluxes, most noticeably enhancing global cumulative ELUC by 33PgC(1750-2014) and entailing a significant reduction in carbon stored in vegetation, although the effect on soil C stocks was limited. Simulations demonstrated that assessments of historical carbon stocks and fluxes are highly uncertain due to the choice of LUC reconstruction and that the consideration of different contrasting LUC reconstructions is needed to account for this uncertainty. The analysis of gross, in addition to net, land-use changes showed that the full complexity of gross land-use changes is required in order to accurately predict the magnitude of LUC change emissions. This introduces technical challenges to process-based models and relies on extensive information regarding historical land-use transitions.
|
|
| 5. |
- Beard, David J., et al.
(författare)
-
Considerations and methods for placebo controls in surgical trials (ASPIRE guidelines)
- 2020
-
Ingår i: The Lancet. - 0140-6736. ; 395:10226, s. 828-838
-
Forskningsöversikt (refereegranskat)abstract
- Placebo comparisons are increasingly being considered for randomised trials assessing the efficacy of surgical interventions. The aim of this Review is to provide a summary of knowledge on placebo controls in surgical trials. A placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. This Review outlines what a placebo control entails and present understanding of this tool in the context of surgery. We consider when placebo controls in surgery are acceptable (and when they are desirable) in terms of ethical arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be done and interpreted. Use of placebo controls is justified in randomised controlled trials of surgical interventions provided there is a strong scientific and ethical rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with high risk of bias, particularly because of the placebo effect. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. This Review forms an outline for best practice and provides guidance, in the form of the Applying Surgical Placebo in Randomised Evaluations (known as ASPIRE) checklist, for those considering the use of a placebo control in a surgical randomised controlled trial.
|
|
| 6. |
- Beard, David J., et al.
(författare)
-
Placebo comparator group selection and use in surgical trials : The aspire project including expert workshop
- 2021
-
Ingår i: Health Technology Assessment. - 1366-5278. ; 25:53
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. Objectives: To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. Design: To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. Setting: A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. Results: To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. Conclusions: The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. Limitations: Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. Future work: Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space.
|
|
| 7. |
- Cuppen, Edwin, et al.
(författare)
-
Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care
- 2022
-
Ingår i: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE The combination of whole-genome and transcriptome sequencing (WGTS) is expected to transformdiagnosis and treatment for patients with cancer. WGTS is a comprehensive precision diagnostic test that isstarting to replace the standard of care for oncology molecular testing in health care systems around the world;however, the implementation and widescale adoption of this best-in-class testing is lacking.METHODS Here, we address the barriers in integrating WGTS for cancer diagnostics and treatment selection andanswer questions regarding utility in different cancer types, cost-effectiveness and affordability, and otherpractical considerations for WGTS implementation.RESULTS We review the current studies implementing WGTS in health care systems and provide a synopsis of theclinical evidence and insights into practical considerations for WGTS implementation. We reflect on regulatory,costs, reimbursement, and incidental findings aspects of this test.CONCLUSION WGTS is an appropriate comprehensive clinical test for many tumor types and can replacemultiple, cascade testing approaches currently performed. Decreasing sequencing cost, increasing number ofclinically relevant aberrations and discovery of more complex biomarkers of treatment response, should pave theway for health care systems and laboratories in implementing WGTS into clinical practice, to transform diagnosisand treatment for patients with cancer.
|
|
| 8. |
- Huyghe, Jeroen R., et al.
(författare)
-
Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
-
Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
|
|
| 9. |
- Kondo, Masayuki, et al.
(författare)
-
Are Land-Use Change Emissions in Southeast Asia Decreasing or Increasing?
- 2022
-
Ingår i: Global Biogeochemical Cycles. - 0886-6236. ; 36:1
-
Tidskriftsartikel (refereegranskat)abstract
- Southeast Asia is a region known for active land-use changes (LUC) over the past 60 years; yet, how trends in net CO2 uptake and release resulting from LUC activities (net LUC flux) have changed through past decades remains uncertain. The level of uncertainty in net LUC flux from process-based models is so high that it cannot be concluded that newer estimates are necessarily more reliable than older ones. Here, we examined net LUC flux estimates of Southeast Asia for the 1980s−2010s from older and newer sets of Dynamic Global Vegetation Model simulations (TRENDY v2 and v7, respectively), and forcing data used for running those simulations, along with two book-keeping estimates (H&N and BLUE). These estimates yielded two contrasting historical LUC transitions, such that TRENDY v2 and H&N showed a transition from increased emissions from the 1980s to 1990s to declining emissions in the 2000s, while TRENDY v7 and BLUE showed the opposite transition. We found that these contrasting transitions originated in the update of LUC forcing data, which reduced the loss of forest area during the 1990s. Further evaluation of remote sensing studies, atmospheric inversions, and the history of forestry and environmental policies in Southeast Asia supported the occurrence of peak emissions in the 1990s and declining thereafter. However, whether LUC emissions continue to decline in Southeast Asia remains uncertain as key processes in recent years, such as conversion of peat forest to oil-palm plantation, are yet to be represented in the forcing data, suggesting a need for further revision.
|
|
| 10. |
- Kondo, Masayuki, et al.
(författare)
-
State of science in carbon budget assessments for temperate forests and grasslands
- 2022
-
Ingår i: Balancing Greenhouse Gas Budgets : Accounting for Natural and Anthropogenic Flows of CO2 and other Trace Gases - Accounting for Natural and Anthropogenic Flows of CO2 and other Trace Gases. - 9780128149522 - 9780128149539 ; , s. 237-270
-
Bokkapitel (refereegranskat)abstract
- With the abundance of observations and advancement in modeling, temperate regions allow for a comprehensive comparison of the data-driven and process-based methods of carbon budget estimation. This chapter presents a review of the latest methodologies for carbon budget and component flux estimation, and the key components in the temperate carbon budget, such as forest regrowth, and summarizes uncertainties in the current carbon budget of temperate ecosystems that the research community needs to resolve. Lastly, we describe the key progress made in the carbon budget assessment in past decades, and how it should be further advanced to be useful for policy decision-making.
|
|
